Tryptase inhibitors

Abstract

Compounds of formula (I) in which M, B1, B2, B3, B4, B5, B6, A1, A2, A3, A4, A5, A6, K1 and K2 have the meanings as indicated in the description, are novel effective tryptase inhibitors.

1. A compound of formula I                  
 
       in which
 A1 and A2 are identical or different and are —O—, —C(O)—, —O—C(O)—, —NH—C(O)— or a bond, 
 A3 and A4 are identical or different and are 1,4-piperazinylene or a bond, 
 A5 and A6 are identical or different and are —C(O)—, —C(O)—NH—, —NH—C(O)— or —NH—C(O)—NH—, 
 M is the central building block                  
 
 K1 is —B7—(C(O)) m —B9—Y1 or —B7—(C(O)) m —B9—Z1—B11—X1, 
 K2 is —B8—(C(O)) p —B10—Y2 or —B8—(C(O)) p —B10—Z 2 —B 12—X2, 
 B1 and B2 are identical or different and are a bond or methylene, 
 B3, B4, B5 and B6 are identical or different and are a bond or 1–3C-alkylene, 
 B7, B8, B9 and B10 are identical or different and are a bond or 1–4C-alkylene, 
 B11 and B12 are identical or different and are a bond or methylene, 
 m is 0, 
 p is 0, 
 X1 and X2 are identical or different and are selected from the groups below                  
 
 Y1 and Y2 are imidizol-1-yl, 
 Z1 and Z2 are identical or different and are 5,2-pyridinylene, 6-methyl-5,2-pyridinylene, 4,1-piperidinylene, 3,6-indazolylene, 3,6-indolylene, 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene or 1,4-cyclohexylene, 
 and where on the direct route along the bonds between the terminal nitrogen atom as defined in K1 on the one hand and the terminal nitrogen atom as defined in K2 on the other hand, 20 to 40 bonds have to be present, wherein each double bond is counted as one bond and each triple bond is counted as one bond, or a solvate, hydrate, salt, hydrate of a salt or solvate of a salt thereof, or an N-oxide of the nitrogen-containing heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes, or a hydrate, salt or hydrate of a salt thereof, 
 wherein the compounds in which one or more of the variables B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11 or B12 may assume the meaning of a bond resulting in the direct linkage of two heteroatoms or carbonyl groups are excluded. 
 
     
     
       2. A compound of formula I according to  claim 1 , in which
 A1 and A2 are —O—C(O)—, 
 A3 and A4 are 1,4-piperazinylene, 
 A5 and A6 are identical or different and are —C(O)— or —C(O)—NH—, 
 M is a central building block selected from the groups below                  
 
 K1 is —B7—(C(O)) m —B9—Z1—B11—X1, 
 K2 is —B8—(C(O)) p —B10—Z2—B12—X2, 
 B1, B2, B3, B4, B5 and B6 are a bond, 
 B7 and B8 are identical or different and are a bond or methylene, 
 B9 and B10 are a bond, 
 B11 and B12 are methylene, 
 m is 0, 
 p is 0, 
 X1 and X2 are amino, 
 Z1 and Z2 are identical or different and are 1,4-phenylene or 1,4-cyclohexylene, 
 
       or a hydrate, salt or hydrate of a salt thereof. 
     
     
       3. A compound of formula I according to  claim 1  with the chemical name 
       1,2-bis[4-trans-4-aminomethylcyclohexylcarbonyl)-1-piperazinylcarbonyl-1-oxyprop-2ynyl]benzene; 
       1,4-bis[4-trans-4-aminomethylcyclohexylcarbonyl)-1-piperazinylcarbonyl-1-oxyprop-2ynyl]benzene; 
       1,2-bis[4-(4-aminomethylbenzylaminocarbonyl)-1-piperazinylcarbonyl- 1-oxyprop-2ynyl]benzene; 
       1,3-bis[4-(4-aminomethylbenzylaminocarbonyl)-1-piperazinylcarbonyl- 1-oxyprop-2ynyl]benzene;
 or a hydrate, salt or hydrate of a salt thereof. 
 
     
     
       4. A pharmaceutical composition comprising a compound of  claim 1  or a pharmaceutically acceptable hydrate, salt or hydrate of a salt thereof, or an N-oxide of a compound of  claim 1  or a pharmaceutically acceptable hydrate, salt or hydrate of a salt thereof; and a suitable pharmaceutical excipient. 
     
     
       5. A method of treating a disease or disorder in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable hydrate, salt or hydrate of a salt thereof, or an N-oxide of a compound of  claim 1  or a pharmaceutically acceptable hydrate, salt or hydrate of a salt thereof,
 wherein the disease or disorder is selected from the group consisting of asthma, allergic conjunctivitis, allergic rhinitis, psoriasis, sclerodermatitis and inflammatory bowel disease. 
 
     
     
       6. The method of  claim 5 , wherein the disease or disorder is asthma. 
     
     
       7. A compound of formula I                  
 
       in which
 —B1—A1—B3—A3—B5—A5— and —B2—A2—B4—A4—B6—A6— are identical or different and are selected from the groups below                  
 
 M is the central building block                  
 
 K1 is —B7—(C(O)) m —B9—Y1 or —B7—(C(O)) m —B9—Z1—B11—X1, 
 K2 is —B8—(C(O)) p —B10—Y2 or —B8—(C(O)) p —B10—Z2—B12—X2, 
 B7, B8, B9, B10, B11 and B12 are identical or different and are a bond or 1–2C-alkylene, 
 m is 0, 
 p is 0, 
 X1 and X2 are identical or different and are selected from the groups below                  
 
 Y1 and Y2 are imidizol-1-yl, 
 Z1 and Z2 are identical or different and are 5,2-pyridinylene, 6-methyl-5,2-pyridinylene, 4,1-piperidinylene, 3,6-indazolylene, 3,6-indolylene, 1,3-phenylene, 1,4-phenylene, 1,3-cyclohexylene or 1,4-cyclohexylene, 
 and where on the direct route along the bonds between the terminal nitrogen atom as defined in K1 on the one hand and the terminal nitrogen atom as defined in K2 on the other hand, 20 to 40 bonds have to be present, wherein each double bond is counted as one bond and each triple bond is counted as one bond, or a hydrate, salt or hydrate of a salt thereof, or an N-oxide of the nitrogen-containing heteroaryls, heterocycloalkyls, heteroarylenes and heterocycloalkylenes, or a hydrate, salt or hydrate of a salt thereof. 
 
     
     
       8. A compound of formula I according to  claim 7  in which
 —B1—A1—B3—A3—B5—A5— and —B2—A2—B4—A4—B6—A6— are identical or different and are selected from                  
 
 M is the central building block                  
 
 K1 is —B7—(C(O)) m —B9—Z1—B11—X1, 
 K2 is —B8—(C(O)) p —B10—Z2—B12—X2, 
 B7 and B8 are identical or different and are a bond or methylene, 
 B9 and B10 are a bond, 
 B11 and B12 are methylene, 
 m is 0, 
 p is 0, 
 X1 and X2 are amino, 
 Z1 and Z2 are identical or different and are 1,4-phenylene or 1,3-phenylene, 
 or a hydrate, salt or hydrate of a salt thereof. 
 
     
     
       9. A compound of formula I according to  claim 7  with the chemical name 
       1,3-Bis-(4-aminomethylbenzylaminocarbonyl-1-oxyprop-2ynyl)-benzene; 
       1,2-Bis-(4-aminomethylbenzylaminocarbonyl-1-oxyprop-2ynyl)-benzene; 
       1,4-Bis-(4-aminomethylbenzylaminocarbonylmethyl-1-oxyprop-2-ynyl)-benzene; 
       1,3-Bis-(4-aminomethylbenzylaminocarbonylmethyl-1-oxyprop-2-ynyl)-benzene; 
       1,4-Bis-(4-aminomethylbenzylcarbonyl-1-aminoprop-2-ynyl)-benzene; 
       1,2-Bis-(4-aminomethylbenzylcarbonyl-1-aminoprop-2-ynyl)-benzene; 
       1,4-Bis-(4-aminomethylphenylethylcarbonyl-1-aminoprop-2ynyl)-benzene;
 or a hydrate, salt or hydrate of a salt thereof. 
 
     
     
       10. A pharmaceutical composition comprising a compound of  claim 7  or a pharmaceutically acceptable hydrate, salt or hydrate of a salt thereof, or an N-oxide of a compound of  claim 7  or a pharmaceutically acceptable hydrate, salt or hydrate of a salt thereof; and a suitable pharmaceutical excipient. 
     
     
       11. A method of treating a disease or disorder in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 7  or a pharmaceutically acceptable hydrate, salt or hydrate of a salt thereof,
 or an N-oxide of a compound of  claim 7  or a pharmaceutically acceptable hydrate, salt or hydrate of a salt thereof, 
 wherein the disease or disorder is selected from the group consisting of asthma, allergic conjunctivitis, allergic rhinitis psoriasis, sclerodermatitis and inflammatory bowel disease. 
 
     
     
       12. The method of  claim 11 , wherein the disease or disorder is asthma.